One invention relates to prophylaxis or treatment of pathologic conditions involving constriction or proliferation of smooth muscle or of disease associated with cysteine-containing proteins. A different invention relates to prophylaxis or treatment of a patient in need of a nitric oxide donor and increased blood pressure. Still another invention is directed to prophylaxis or treatment of cardiovascular syndromes.
Nitric oxide (NO) donors are known to be useful for therapeutic utility, e.g., to prevent restenosis following angioplasty (Groves, P., et al., Cardiovascular Research 26, 615-619 (1992)), to inhibit platelets to prevent coagulation and thrombus formation (Groves, P., et al., Circulation 87, 590-597 (1993)) and to treat angina (Knight, et al., Circulation 95, 125-132 (1997)). NO donors are considered to have additional therapeutic utility in cancer, killing microbes and viruses, relaxing airways and intestinal smooth muscle (e.g., for treating asthma and esophageal spasms), in promoting erectile function and in treatment of heart failure and urinary incontinence. The dosages used and considered to be necessary have, at the very least, the effect of lowering systemic blood pressure and pulmonary artery pressure, by relaxing of smooth muscle, a result which has been viewed as a basis for efficacy. In many cardiovascular syndromes, e.g., myocardial infarction and heart failure, standard therapy involves maximal non-harmful lowering of blood pressure as this lowers stress on the heart.
It has been discovered herein that NO donors, as defined herein, can block constriction and thus ameliorate (and prophylax against) pathological constriction of smooth muscle at doses below those that relax smooth muscle and can desensitize receptors at doses that have no effect on vascular tone.
One embodiment of an invention herein, denoted the first embodiment, is directed at a method for prophylaxis or treatment of a patient with a pathologic condition involving constriction or proliferation of smooth muscle, e.g., diseases of the vasculature, or who is at risk for such, except for a patient having acute thrombotic complications of restenosis or platelet embolism or other thromboembolic event (e.g., pulmonary embolism or embolic stroke secondary to endocarditis), said method comprising administering an NO donor which is capable of acutely lowering mean arterial blood pressure or pulmonary artery pressure by more than 10% to said patient in a therapeutically effective amount which is insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure by more than 10%, e.g., by more than 5% (i.e., by amounts that would be otherwise viewed as non-therapeutic). The exception for acute thrombotic complications of restenosis is because Langford, E. J., et al., Lancet 344, 1458-460 (1994) describes low dose administration of NO donor in the setting of putting in a stent and because Kaposzta, Z., et al., Circulation 103, 2371-2375 (2001) shows low dose administration of NO donor decreases platelet embolism and because S-nitrosoglutathione has been shown previously to inhibit other thromboembolic events at doses that do not acutely drop blood pressure reflecting a more potent effect on platelets than on blood pressure. However, there has been no disclosure previously of use of NO donors as defined herein, to treat disorders of blood vessels without acutely dropping blood pressure or directly affecting tone in these vessels, e.g., for treatment of vasospasms or long term antiproliferation or antiatherogenic effect or long term amelioration of systemic hypertension or pulmonary hypertension.
Another embodiment of the invention herein, denoted the second embodiment, is directed to a method for prophylaxis or treatment of a patient with a disease associated with a receptor having a cysteine residue or other cysteine containing protein that is modified by NO donor to alter its function, or at risk therefor, comprising administering an NO donor which is capable of acutely lowering mean arterial blood pressure or pulnonary artery pressure by more than 10% to said patient in a therapeutically effective amount which is insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure more than 10%, e.g., by more than 5%. The term xe2x80x9cdisease associated withxe2x80x9d is used herein to mean a disease in which over or under activation of the receptor or other protein is implicated in the disease.
The term xe2x80x9cacutely lower mean arterial blood pressure or pulmonary artery pressure more than 10%, e.g., by more than 5%,xe2x80x9d is used herein to mean lowering of mean arterial blood pressure or pulmonary artery pressure more than 10%, e.g., by more than 5%, by a single dose of a drug over the period of the half-life of the drug.
Pulmonary artery pressures are measured in the pulmonary artery according to a standard method using a Swan-Ganz catheter.
The first and second embodiments are directed to prophylaxis or treatment. The treatment can involve patients without symptoms in an inactive state of disease to prevent or delay reoccurrence in response to an aggravating stimulus. For example, in the cases of unstable angina or asthma, a patient may be in an inactive status, but symptoms will recur rapidly in response to aggravating stimulus. Thus treatment can be of the disease where symptoms have already been relieved or reduced but sensitivity to aggravating stimulus persists.
A different invention herein, denoted the third embodiment, is directed to treating a patient in need of an NO donor and increased blood pressure, comprising administering a therapeutically effective amount of NO donor directly into an artery of the patient (in distinction to other routes of administration).
Still another invention herein, denoted the fourth embodiment, is directed to a method for the prophylaxis or treatment of a patient with a cardiovascular syndrome, or at risk therefor, comprising administering a therapeutically effective amount of thiol which is insufficient to acutely lower mean arterial blood pressure or pulmonary artery pressure by more than 10%, e.g., by more than 5%.
Usefulness of the result of not acutely lowering blood pressure in some cases is supported by Bing, R. J., et al., Biochem. Biophys. Res. Com. 275, 350-353 (2000).